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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Substitution in the alpha 3 domain of class I molecules can ablate the recognition of target cells by CD8 dependent cytotoxic T lymphocytes. This effect has been attributed to a destruction of the CD8 alpha binding site on the class I molecule, a hypothesis which is consistent with results obtained in conjugate binding assays. To assess the relative contribution to CTL activation of CD8 functioning as either a coreceptor or an accessory molecule, we have compared the ability of H-2Kb ovalbumin reactive CTL to lyse M12.C3 or T2 cells transfected with an H-2Kb gene encoding a wild type or mutant (CD8 nonbinding) alpha 3 domain. To establish that the substitution in the alpha 3 domain does not alter the ability of the H-2Kb molecule to bind the antigenic peptide, we have compared the binding of the ovalbumin derived H-2Kb restricted peptide (SIINFEKL) to T2 cells expressing either the CD8 binding or the CD8 nonbinding form of H-2Kb. This peptide conjugated with FITC bound equally well to T2 cells expressing either form of H-2Kb. Upon binding of this peptide, both forms of the H-2Kb molecule underwent the same conformational change as revealed by increases in the expression of particular serological epitopes. Furthermore, inhibition of the binding of the SIINFEKL peptide to both the wild type and mutant H-2Kb was observed following pretreatment of the cells with similar amounts of other H-2Kb restricted peptides derived from Sendai and Vesicular Stomatitis viruses. When the transfected M12 cells were tested for their ability to serve as targets for an anti-H-2Kb ovalbumin CTL clone, cells expressing the mutant H-2Kb molecule required the addition of 100-fold more exogenous peptide than did cells expressing the wild type molecule in order to obtain significant lysis. These data strengthen the previous hypothesis that CD8 functions much more efficiently as a coreceptor than as an accessory molecule for T cell effector function.
Mol Immunol 1994 Aug
PMID:Analysis of coreceptor versus accessory molecule function of CD8 as a correlate of exogenous peptide concentration. 806 71

Inflammation of heart tissue is a pathological feature of infections and autoimmune diseases, and sometimes also occurs after heart transplantation. In these situations, the invasive infiltration of lymphocytes, most probably cytotoxic (CD8-positive) T cells, is likely to be the cause of cardiac damage, as shown by the results of studies on experimental animal models of myocarditis. However, the cellular and molecular events underlying the interactions between lymphocytes and cardiomyocytes have hitherto not been investigated. In the present study we describe a new procedure for obtaining ventricular heart cells from neonatal mice and for maintaining them in serum-free medium in culture dishes coated with certain matrix components. Such cells adhered, spread, and were functionally active since they started a beating rhythm after 2 days. T and B cells which had been surface-labelled with biotin were added to these cells and lymphocyte adhesion was measured. The number of lymphocytes which became bound to the cardiomyocytes was calculated from the amount of biotin which remained associated with the monolayer after extensive washing to remove non-adherent cells. Colourimetric detection, using a streptavidin-peroxidase reagent, showed that an average of approximately 10 activated lymphocytes bound per heart cell, four times greater than the attachment of resting T cells. The results of this study provide a reproducible basis for using monoclonal antibodies which react against lymphocyte surface receptors and their cognate ligands to identify the specific adhesion molecules involved in heart cell recognition and interaction.
J Mol Cell Cardiol 1994 May
PMID:Interactions between cardiomyocytes and lymphocytes in tissue culture: an in vitro model of inflammatory heart disease. 807 17

The cytoplasmic segment of the CD8 alpha polypeptide includes both a cysteine-containing motif that is required for its association with the tyrosine kinase p56lck, and two serine residues which are likely to be phosphorylated and involved in inside-out signaling phenomena. To determine the relative importance of these residues for CD8 function, a mouse T cell hybridoma expressing a T cell receptor specific for the class I major histocompatibility product H-2Kb was transfected with a set of CD8 alpha chain genes encoding polypeptides in which the cytoplasmic cysteine or serine residues were substituted with alanine. When challenged with Kb-transfected L cells, T cell transfectants expressing CD8 alpha beta or CD8 alpha alpha dimers with substituted cytoplasmic serine residues responded nearly as well as wild-type CD8 transfectants. In marked contrast, the CD8 alpha polypeptides bearing substitutions of both cytoplasmic cysteine residues were totally impaired in their ability to complement the co-expressed T cell receptor.
Mol Immunol 1993 Jun
PMID:The cysteine residues in the cytoplasmic tail of CD8 alpha are required for its coreceptor function. 809 95

The phosphorylation and dephosphorylation of proteins on tyrosyl residues are key regulatory mechanisms in T-cell signal transduction and are controlled by the opposing activities of protein tyrosine kinases and phosphotyrosyl phosphatases (PTPs). In T cells, several nontransmembrane protein tyrosine kinases are associated with receptors; for example, Lck is bound to the coreceptors CD4 and CD8 and becomes activated upon their stimulation. In comparison, little is known about the role of nontransmembrane PTPs in early T-cell signaling. SH-PTP1 (PTP1C, HCP, SHP) is a nontransmembrane PTP expressed primarily in hematopoietic cells, including T cells. We have found that SH-PTP1 is basally phosphorylated on serine in resting T cells. Upon stimulation of CD4 or CD8 either in a T-cell hybridoma cell line or in primary thymocytes, SH-PTP1 becomes tyrosyl phosphorylated. Moreover, SH-PTP1 is constitutively phosphorylated on tyrosine in the Lck-overexpressing lymphoma cell line LSTRA. SH-PTP1 is also a good substrate for recombinant Lck in vitro. Comparisons of the tryptic phosphopeptide maps of wild-type SH-PTP1 and deletion and point mutations establish that the two sites (Y-536 and Y-564) which are directly phosphorylated by Lck in vitro are also phosphorylated in vivo in LSTRA cells. One of these sites (Y-564) is phosphorylated in T cells in response to Lck activation. We conclude that SH-PTP1 undergoes Lck-dependent tyrosyl phosphorylation in T cells and likely plays a role in early T-cell signaling.
Mol Cell Biol 1994 Mar
PMID:Lck-dependent tyrosyl phosphorylation of the phosphotyrosine phosphatase SH-PTP1 in murine T cells. 811 15

The tyrosine protein kinase p56lck transduces signals important for antigen-induced T-cell activation. In transgenic mice, p56lck is oncogenic when overexpressed or expressed as a mutant, catalytically activated enzyme. In humans, the LCK gene is located at the breakpoint of the t(1;7)(p34;q34) chromosomal translocation. This translocation positions the beta T-cell receptor constant region enhancer upstream of the LCK gene without interrupting the LCK coding sequences, and a translocation of this sort occurs in both the HSB2 and the SUP-T-12 T-cell lines. We have found that, although the level of the p56lck protein in HSB2 cells is elevated approximately 2-fold in comparison with that in normal T-cell lines, total cellular tyrosine protein phosphorylation is elevated approximately 10-fold. Increased levels of phosphotyrosine in HSB2 cells resulted from mutations in the LCK gene that activated its function as a phosphotransferase and converted it into a dominant transforming oncogene. The oncogenic p56lck in HSB2 cells contained one amino acid substitution within the CD4/CD8-binding domain, two substitutions in the kinase domain, and an insertion of Gln-Lys-Pro (QKP) between the SH2 and kinase domains. In NIH 3T3 fibroblasts, three of these mutations cooperated to produce the fully oncogenic form of this p56lck variant. These results suggest that mutation of LCK may contribute to some human T-cell leukemias.
Mol Cell Biol 1994 Apr
PMID:Oncogenic activation of the Lck protein accompanies translocation of the LCK gene in the human HSB2 T-cell leukemia. 813 46

Repeated injections of mitomycin C-treated T2 fibrosarcoma cells into tumor-sensitized mice cause regression of a secondary tumor graft and more than 90% of the mice are cured. In the data presented here, an enhancement of the cytolytic cell-mediated activities measured in vitro against the specific T2 targets is shown in lymph nodes draining the tumor and in the spleen during the process of tumor rejection. Histopathologic studies revealed a rapid and marked accumulation of mononuclear cells mostly at the periphery of the rejected tumor tissue. A significant increase of CD8-positive, asialo GM1-positive and acid phosphatase-positive cells was observed in the rejected tumors whereas CD4-positive cells were similarly detected in both progressing and rejected tumor tissue. As macrophages seemed to be the population presenting the most persistent variation after immunization, the production of TNF-alpha was studied within the tumor site and in the lymphoid tissues during the regression process. Firstly, the presence of TNF-alpha within the cytoplasm of most of the adherent cell fractions isolated from the spleen and the tumor of immune mice was demonstrated by immunocytochemistry. Next, TNF-alpha mRNA-containing cells were determined by in situ hybridization of frozen tumor sections and identified essentially as tumor infiltrating macrophages. Finally, the macrophage populations isolated from tumors and from the spleen of immune mice were able to produce in vitro large quantities of TNF-alpha without exogenous stimulation. These findings support the role of TNF-alpha in the effector mechanisms contributing to the tumor regression process.
Virchows Arch B Cell Pathol Incl Mol Pathol 1993
PMID:Phenotypical and functional analyses of mononuclear cells during rejection of a transplanted murine fibrosarcoma. 814 54

We have previously shown that CTL and NK cells rapidly down regulate perforin mRNA and become functionally inactive within 4-6 hr after exposure to sensitive target cells (TC). We report here for the first time that CTL also down regulate perforin mRNA upon exposure to resistant, but binding, TC. When three separate human MHC-restricted CTL lines were exposed to resistant TC, perforin mRNA was rapidly degraded. Removal of both extracellular Ca++ and Mg++ prevented perforin message down regulation, whereas removal of Ca++ alone did not, indicating that CTL:TC binding was required. Unlike the response of CTL exposed to sensitive TC, resistant TC did not trigger serine esterase (SE) release, suggesting distinct signalling pathways for perforin mRNA down regulation and granule exocytosis. Moreover, using western analysis, we showed that there was limited (< 10%) perforin protein release after CTL:TC interaction, suggesting that CTL loss of lytic activity after exposure to sensitive TC is not due to massive depletion of perforin. Treatment of CTL with mAb to CD2, CD3, CD2 + CD3, CD8, Class I and LFA-1 did not induce perforin mRNA down regulation. Furthermore, mAb to CD2, CD3, CD8, Class I, Class II, CD54 and LFA-1 did not block TC-mediated perforin mRNA down regulation although lysis of TC was inhibited.
Mol Immunol 1994 Apr
PMID:Target cell-directed degradation of perforin mRNA in CTL: lack of correlation with loss of protein and lytic ability. 815 43

The membrane-spanning and cytoplasmic domains of CD4 and CD8 were replaced by those of TGN38. After transient expression in HeLa cells, the location of the hybrid proteins was determined using immunofluorescence and quantitative immuno-electron microscopy, FACS analysis and metabolic labeling. The membrane-spanning domain was found to contain a signal that localized hybrid proteins to the TGN. This was in addition to the signal previously identified in the cytoplasmic domain (Bos, K., C. Wraight, and K. Stanley. 1993. EMBO (Eur. Mol. Biol. Organ) J. 12:2219-2228. Humphrey, J. S., P. J. Peters, L. C. Yuan, and J. S. Bonifacino. 1993. J. Cell Biol. 120:1123-1135. Wong, S. H., and W. Hong. 1993. J. Biol. Chem. 268:22853-22862). The different properties of these two signals suggest that each operates by a different mechanism.
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PMID:The TGN38 glycoprotein contains two non-overlapping signals that mediate localization to the trans-Golgi network. 816 44

T-cell activation requires two signaling events. One is provided by the engagement of the T-cell antigen receptor, and the second represents a costimulatory signal provided by antigen-presenting cells. CD28 mediates a costimulatory signal by binding its ligands, B7-1 and B7-2, on antigen-presenting cells, but the signaling pathway activated by CD28 has not been identified. A homologous molecule, CTLA-4, expressed on activated T cells, also binds to B7-1 and B7-2, but whether it has a signaling function is not known. We performed a structure-function analysis of CD28 to identify the functional domain which activates signal transduction. Truncation of the 40-amino-acid CD28 cytoplasmic tail abrogated costimulatory signaling. Chimeric constructs containing the extracellular and transmembrane regions of CD8 linked to the cytoplasmic region of CD28 had a costimulatory signaling function. Similar chimeras containing the cytoplasmic tail of CTLA-4 did not signal. Thus, the cytoplasmic region of CD28, but not CTLA-4, is sufficient to mediate costimulatory signaling. In addition, after CD28 stimulation, the p85 subunit of phosphatidylinositol 3'-kinase and phosphatidylinositol 3'-kinase activity were found in CD28 immunoprecipitates. The CD8-CD28 chimera, which has a costimulatory signaling function, associates with p85, while the nonfunctioning CD8-CTLA-4 chimera and a CD8-zeta chimera do not associate with p85. These results suggest that phosphatidylinositol 3'-kinase is specifically activated by CD28 and may mediate proximal events in the costimulatory signaling pathway regulated by CD28.
Mol Cell Biol 1994 May
PMID:The cytoplasmic domain of CD28 is both necessary and sufficient for costimulation of interleukin-2 secretion and association with phosphatidylinositol 3'-kinase. 816 87

On the basis of similarities in sequence and structure, the protein domains that form the immunoglobulin superfamily have been divided into three sets: one with variable-like domains, the V set, and two with different variants of the constant-like domains, the C1 and C2 sets. Examination of a muscle member of the immunoglobulin superfamily, telokin, shows that its structure is closely related to those of the variable domains found in antibodies, CD2, CD4 and CD8. However, it also contains structural features that, previously, have only been found in constant domains. Telokin represents a new structural set in the superfamily which we call the I set. Using the structures of telokin, and variable domains from antibodies, CD4 and CD8, we constructed a profile that describes the sequence characteristics of the structural core common to those proteins. This sequence profile makes a good match to the sequences of many of the immunoglobulin superfamily domains that form the cell adhesion molecules and surface receptors. This match implies that these domains also have structures that belong to the I set.
J Mol Biol 1994 May 13
PMID:Many of the immunoglobulin superfamily domains in cell adhesion molecules and surface receptors belong to a new structural set which is close to that containing variable domains. 817 43


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